This invention relates to inhibitors of beta amyloid production, which have utility in the treatment of Alzheimer's disease.
Alzheimer's Disease (AD) is the most common form of dementia (loss of memory) in the elderly. The main pathological lesions of AD found in the brain consist of extracellular deposits of beta amyloid protein in the form of plaques and angiopathy and intracellular neurofibrillary tangles of aggregated hyperphosphorylated tau protein. Recent evidence has revealed that elevated beta amyloid levels in the brain not only precede tau pathology but also correlate with cognitive decline. Further suggesting a causative role for beta amyloid in AD, recent studies have shown that aggregated beta amyloid is toxic to neurons in cell culture.
Beta amyloid protein is composed mainly of 39-42 amino acid peptides and is produced from a larger precursor protein called amyloid precursor protein (APP) by the sequential action of the proteases beta and gamma secretase. Although rare, cases of early onset AD have been attributed to genetic mutations in APP that lead to an overproduction of either total beta amyloid protein or its more aggregation-prone 42 amino acid isoform. Furthermore, people with Down's Syndrome possess an extra chromosome that contains the gene that encodes APP and thus have elevated beta amyloid levels and invariably develop AD later in life.
Heterocyclic sulfonamide inhibitors of beta amyloid production have been described. U.S. Pat. No. 6,878,742 (2005) and U.S. Pat. No. 6,610,734 (2003). Fluoro-and trifluoroalkyl-containing heterocyclic sulfonamide inhibitors of beta amyloid production have also been described in U.S. Patent Application Publication No. US2004/0198778.
There continues to be a need for compositions useful in inhibiting beta amyloid production and in the treatment of the effects of Alzheimer's Disease (AD).